WO2014187943A1 - Treatment or prevention of depression using menthol and/or icilin - Google Patents

Treatment or prevention of depression using menthol and/or icilin Download PDF

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Publication number
WO2014187943A1
WO2014187943A1 PCT/EP2014/060634 EP2014060634W WO2014187943A1 WO 2014187943 A1 WO2014187943 A1 WO 2014187943A1 EP 2014060634 W EP2014060634 W EP 2014060634W WO 2014187943 A1 WO2014187943 A1 WO 2014187943A1
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WO
WIPO (PCT)
Prior art keywords
depression
composition
menthol
icilin
group
Prior art date
Application number
PCT/EP2014/060634
Other languages
English (en)
French (fr)
Inventor
Susana CAMACHO
Stéphanie MICHLIG GONZALEZ
Johannes Le Coutre
Henry Markram
Maurizio PEZZOLI
Original Assignee
Nestec S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nestec S.A. filed Critical Nestec S.A.
Priority to AU2014270339A priority Critical patent/AU2014270339A1/en
Priority to US14/892,016 priority patent/US20160108005A1/en
Priority to CA2908378A priority patent/CA2908378A1/en
Priority to JP2016514430A priority patent/JP2016524609A/ja
Priority to CN201480029644.1A priority patent/CN105263481A/zh
Priority to EP14726946.8A priority patent/EP3003294A1/en
Priority to BR112015028884A priority patent/BR112015028884A2/pt
Publication of WO2014187943A1 publication Critical patent/WO2014187943A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic
    • C07C35/08—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic containing a six-membered rings
    • C07C35/12—Menthol
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present disclosure generally relates to methods and compositions for prevention or treatment of depression. More specifically, the present disclosure relates to compositions comprising at least one of Menthol or Icilin and further relates to methods comprising administering such compositions.
  • Severe depression is a long lasting and recurring disease, which is usually poorly diagnosed. Furthermore, many patients suffer from mild or moderately severe depression. Conventional anti-depressants still have many limitations that hinder the effective treatment of depression.
  • the glutamatergic system may be a potential target for anti-depressant therapy.
  • Glutamate antagonists inhibit the binding of glutamate to NMDA receptors such that accumulation of Ca 2+ and therefore excitotoxicity can be avoided.
  • use of glutamate antagonists presents a huge obstacle because the treatment interferes with the normal action of glutamate under standard conditions.
  • the present inventors surprisingly and unexpectedly found that an active compound from spices, the transient receptor potential M8 (TRPM8) channel agonist Menthol, can depress neuronal activity in the neocortex and the amygdale.
  • TRPM8 transient receptor potential M8
  • the present inventors discovered the same effect with Icilin, a synthetic super-agonist of the TRPM8 ion channel, even though the structure of Icilin is not related to Menthol.
  • the present disclosure provides a method for treating depression.
  • the method comprises administering to an individual having depression a therapeutically effective amount of a compound selected from the group consisting of Menthol, Icilin and combinations thereof.
  • the depression is selected from the group consisting of unipolar depression, bipolar depression, acute depression, chronic depression, sub-chronic depression, dysthymia, postpartum depression, climacteric depressive symptoms, seasonal affective disorders, and combinations thereof.
  • the composition is administered periodically for at least one year.
  • the composition can be administered daily.
  • the composition is selected from the group consisting of a medicament, a food product, and a supplement to a food product.
  • a method for preventing depression comprises administering to an individual at risk of same a therapeutically effective amount of a compound selected from the group consisting of menthol, icilin and combinations thereof.
  • the depression is selected from the group consisting of unipolar depression, bipolar depression, acute depression, chronic depression, sub-chronic depression, dysthymia, postpartum depression, climacteric depressive symptoms, seasonal affective disorders, and combinations thereof.
  • the composition is administered periodically for at least one year.
  • the composition can be administered daily.
  • the composition is selected from the group consisting of a medicament, a food product, and a supplement to a food product.
  • a composition for treating or preventing depression comprises a therapeutically effective amount of a compound selected from the group consisting of Menthol, Icilin and combinations thereof.
  • the composition is the composition is a medicament.
  • the composition is a food product.
  • the food product can comprise a component selected from the group consisting of protein, carbohydrate, fat and combinations thereof.
  • the composition is a supplement to a food product.
  • An advantage of the present disclosure is to prevent or treat depression more effectively and/or more safely than glutamate antagonists.
  • Another advantage of the present disclosure is to prevent or treat depression without interfering with the normal action of glutamate under standard conditions.
  • Still another advantage of the present disclosure is to prevent or treat depression with compounds that can be easily and safely used in food products.
  • Yet another advantage of the present disclosure is to prevent or treat depression by targeting the pre-synaptic phase of neuronal firing.
  • An additional advantage of the present disclosure is to prevent or treat depression by targeting the pre-synaptic phase of neuronal firing while reducing the possibility of excitotoxicity.
  • Another advantage of the present disclosure is to prevent or treat depression with naturally-occurring compounds that can be found in spices.
  • Still another advantage of the present disclosure is to prevent or treat depression with tolerable side effects or no side effects.
  • Figure 1 shows the chemical structures of compounds that can be used in embodiments of the composition according to the present disclosure.
  • Figure 2 shows charts of whole cell, current clamp recordings in a Lateral Amygdala glutamatergic neuron (in a mouse brain slice) in the absence (control) and presence of TRPM8 ligands (Linalool, Icilin or Menthol).
  • Figure 3 shows a chart of whole cell, current clamp recordings in a Lateral Amygdala glutamatergic neuron (in a mouse brain slice) with increasing concentration of gabazine (GABA A blocker) applied extracellularly during recordings of 5 min each (washout lO min).
  • GABA A blocker gabazine
  • Figure 4 shows a chart of whole cell, current clamp recordings in a Lateral Amygdala glutamatergic neuron (in a mouse brain slice) showing enhanced detail of a burst.
  • Figure 5 shows a chart of whole cell, current clamp recordings in a Lateral Amygdala glutamatergic neuron (in a mouse brain slice) with increasing concentration of gabazine (GABA A blocker) applied extracellularly during recordings of 5 min each (washout 10 min) while 10 minutes previous to and during the exposure of the different concentrations of gabazine, 250 ⁇ menthol was also applied extracellularly.
  • GABA A blocker gabazine
  • depression includes, as non-limiting examples, unipolar depression, bipolar depression, acute depression, chronic depression, sub-chronic depression, dysthymia, postpartum depression, climacteric depressive symptoms, and seasonal affective disorders.
  • prevention includes reduction of risk and/or severity of depression.
  • treatment includes both prophylactic or preventive treatment (that prevent and/or slow the development of a targeted pathologic condition or disorder) and curative, therapeutic or disease-modifying treatment, including therapeutic measures that cure, slow down, lessen symptoms of, and/orhalt progression of a diagnosed pathologic condition or disorder; and treatment of patients at risk of contracting a disease or suspected to have contracted a disease, as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition.
  • the term does not necessarily imply that a subject is treated until total recovery.
  • treatment also refer to the maintenance and/or promotion of health in an individual not suffering from a disease but who may be susceptible to the development of an unhealthy condition.
  • treatment also intended to include the potentiation or otherwise enhancement of one or more primary prophylactic or therapeutic measure.
  • treatment also intended to include the dietary management of a disease or condition or the dietary management for prophylaxis or prevention a disease or condition.
  • a treatment can be patient- or doctor-related.
  • a "therapeutically effective amount” is an amount that prevents a deficiency, treats a disease or medical condition in an individual or, more generally, reduces symptoms, manages progression of the diseases or provides a nutritional, physiological, or medical benefit to the individual.
  • Animal includes, but is not limited to, mammals, which includes but is not limited to, rodents, aquatic mammals, domestic animals such as dogs and cats, farm animals such as sheep, pigs, cows and horses, and humans. Where “animal,” “mammal” or a plural thereof is used, these terms also apply to any animal that is capable of the effect exhibited or intended to be exhibited by the context of the passage.
  • the term “patient” is understood to include an animal, especially a mammal, and more especially a human that is receiving or intended to receive treatment, as treatment is herein defined. While the terms “individual” and “patient” are often used herein to refer to a human, the present disclosure is not so limited. Accordingly, the terms “individual” and “patient” refer to any animal, mammal or human, having or at risk for a medical condition that can benefit from the treatment.
  • Food product and “food composition,” as used herein, are understood to include any number of optional additional ingredients, including conventional food additives, for example one or more of proteins, carbohydrates, fats, acidulants, thickeners, buffers or agents for pH adjustment, chelating agents, colorants, emulsifiers, excipients, flavor agents, minerals, osmotic agents, a pharmaceutically acceptable carrier, preservatives, stabilizers, sugars, sweeteners, texturizers and/or vitamins.
  • the optional ingredients can be added in any suitable amount.
  • the present inventors surprisingly and unexpectedly found that an active compound from spices, the transient receptor potential M8 (TRPM8) channel agonist Menthol, can depress neuronal activity in neocortex and amygdale.
  • TRPM8 transient receptor potential M8
  • the present inventors discovered the same effect with Icilin, a synthetic super-agonist of the TRPM8 ion channel, even though the structure of Icilin is not related with Menthol; nevertheless, Icilin produces an extreme sensation of cold both in humans and animals.
  • Icilin target a presynaptic phase of APs, decreasing activity and diminishing glutamate release, which reduces drastically the possibility of reaching excitotoxicity levels; and 2) Menthol and
  • Icilin act stronger in the high stimulation context. In contrast to glutamate antagonists that typically inhibit the binding of glutamate to NMDA receptors, Menthol and Icilin decrease neuronal activity, and target the pre-synaptic phase of the firing to reduce the possibilities of excitotoxicity one step earlier.
  • the composition provided by the present disclosure comprises a therapeutically effective amount of at least one of Menthol or Icilin.
  • depression is treated or prevented by administering to an individual in need of same the composition comprising at least one of Menthol or Icilin.
  • the composition comprising at least one of Menthol or Icilin can be administered to an individual having depression to treat the depression.
  • the depression can be unipolar depression, bipolar depression, acute depression, chronic depression, sub-chronic depression, dysthymia, postpartum depression, climacteric depressive symptoms, seasonal affective disorders, and combinations thereof.
  • the composition can be administered periodically for at least one year, preferably at least two years, more preferably at least three years, even more preferably at least four years, and most preferably at least five years.
  • Each of Menthol and/or Icilin can be administered to the individual in a daily amount of 0.0015 mg/kg of body weight to 400 mg/ kg of body weight, preferably 0.1 mg/kg of body weight to 300 mg/kg of body weight, more preferably 1.0 mg/kg of body weight to 200 mg/kg of body weight, and most preferably 10.0 mg/kg of body weight to 100 mg/kg of body weight.
  • each of Menthol and/or Icilin can be administered to the individual in a daily amount of 0.0015 mg/kg of body weight to 0.01 mg/kg of body weight, 0.01 mg/kg of body weight to 0.1 mg/kg of body weight, 0.1 mg/kg of body weight to 1 .0 mg/kg of body weight, 1.0 mg/kg of body weight to 10.0 mg/kg of body weight, 10.0 mg/kg of body weight to 100.0 mg/kg of body weight, 100.0 mg/kg of body weight to 200.0 mg/kg of body weight, 200.0 mg/kg of body weight to 300.0 mg/kg of body weight, or 300.0 mg/kg of body weight to 400.0 mg/kg of body weight.
  • the composition comprising at least one of Menthol or Icilin may be a medicament, a food product or a supplement to a food product.
  • the supplement may be in the form of tablets, capsules, pastilles or a liquid, for example.
  • the supplement may further contain protective hydrocolloids (such as gums, proteins, modified starches), binders, film forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilizing agents (oils, fats, waxes, lecithins or the like), adsorbents, carriers, fillers, co-compounds, dispersing agents, wetting agents, processing aids (solvents), flowing agents, taste masking agents, weighting agents, jellifying agents and gel forming agents.
  • protective hydrocolloids such as gums, proteins, modified starches
  • binders film forming agents
  • encapsulating agents/materials, wall/shell materials matrix compounds
  • coatings coating
  • the supplement may also contain conventional pharmaceutical additives and adjuvants, excipients and diluents, including, but not limited to, water, gelatin of any origin, vegetable gums, ligninsulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavoring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like.
  • conventional pharmaceutical additives and adjuvants, excipients and diluents including, but not limited to, water, gelatin of any origin, vegetable gums, ligninsulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavoring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like.
  • the supplement can be added in a product acceptable to the consumer as an ingestible carrier or support.
  • Such carriers or supports are a pharmaceutical, a food composition, and a pet food composition.
  • Non-limiting examples for food and pet food compositions are milks, yogurts, curds, cheeses, fermented milks, milk-based fermented products, fermented cereal based products, milk-based powders, human milks, preterm formulas, infant formulas, oral supplements, and tube feedings.
  • the composition comprising at least one of Menthol or Icilin is administered to a human.
  • the composition comprising at least one of Menthol or Icilin is administered to a non-human animal, preferably a cat or a dog.
  • the composition can be provided to a companion animal by its owner.
  • a mouse brain slice was used to study the effects of Menthol, Linalool (another transient receptor potential M8 (TRPM8) channel agonist) and Icilin.
  • the amygdaloid complex is located within the medial temporal lobe in neocortex and amygdala.
  • the lateral and basolateral nuclei of the amygdaloid complex receive sensory information from cortical and thalamic structures, process the information, and then transmit the information, either directly or through the basal nucleus, to the central nucleus.
  • synaptic responses from the basolateral complex can be evoked electrically using electrodes, and the action potentials can be measured.
  • Figure 2 shows recordings in the absence of Menthol, Linalool or Icilin (control) and recordings in the presence of Menthol, Linalool or Icilin.
  • a square pulse of 2.5s was applied at high depolarization of membrane potential (approximately -30 mV).
  • the recordings show that, in the presence of the TRPM8 ligands at high depolarization levels, inactivation of the sodium fast channels happens sooner relative to control, avoiding further neuronal firing.
  • Figure 3 shows recordings in increasing concentrations of gabazine, a GABA A blocker, applied extracellularly during recordings of 5 minutes each with 10 minute washout. As shown, neurons spontaneously present action potential bursts due to massive presynaptic discharges. Figure 4 depicts enhanced detail of one of the bursts and shows that serial action potentials can be observed in a single burst.
  • Figure 5 shows recordings under the same conditions, namely increasing concentrations of gabazine applied extracellularly during recordings of 5 minutes each with 10 minute washout, except that in Figure 5, Menthol 250 ⁇ was applied extracellularly at 10 minutes previous to and during the exposure of the different concentrations of gabazine. As illustrated in the figure, neurons show a complete absence or a strongly decreased presence of spontaneous bursts (compare Figure 5 to Figure 3).

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  • General Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Nutrition Science (AREA)
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  • Neurosurgery (AREA)
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  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
PCT/EP2014/060634 2013-05-24 2014-05-23 Treatment or prevention of depression using menthol and/or icilin WO2014187943A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AU2014270339A AU2014270339A1 (en) 2013-05-24 2014-05-23 Treatment or prevention of depression using Menthol and/or Icilin
US14/892,016 US20160108005A1 (en) 2013-05-24 2014-05-23 Treatment or prevention of depression using menthol and/or icilin
CA2908378A CA2908378A1 (en) 2013-05-24 2014-05-23 Treatment or prevention of depression using menthol and/or icilin
JP2016514430A JP2016524609A (ja) 2013-05-24 2014-05-23 メントール及び／又はイシリンを用いるうつ病の処置又は予防
CN201480029644.1A CN105263481A (zh) 2013-05-24 2014-05-23 使用薄荷醇和/或冰素治疗或预防抑郁
EP14726946.8A EP3003294A1 (en) 2013-05-24 2014-05-23 Treatment or prevention of depression using menthol and/or icilin
BR112015028884A BR112015028884A2 (pt) 2013-05-24 2014-05-23 tratamento ou prevenção de depressão utilizando mentol e/ou icilina

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361827256P 2013-05-24 2013-05-24
US61/827,256 2013-05-24

Publications (1)

Publication Number Publication Date
WO2014187943A1 true WO2014187943A1 (en) 2014-11-27

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2014/060634 WO2014187943A1 (en) 2013-05-24 2014-05-23 Treatment or prevention of depression using menthol and/or icilin

Country Status (8)

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US (1) US20160108005A1 (pt)
EP (1) EP3003294A1 (pt)
JP (1) JP2016524609A (pt)
CN (1) CN105263481A (pt)
AU (1) AU2014270339A1 (pt)
BR (1) BR112015028884A2 (pt)
CA (1) CA2908378A1 (pt)
WO (1) WO2014187943A1 (pt)

Citations (4)

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Publication number Priority date Publication date Assignee Title
US8217060B2 (en) * 2009-05-15 2012-07-10 Janssen Pharmaceutica, Nv Benzimidazole derivatives useful as TRP M8 receptor modulators
US20120190674A1 (en) * 2007-07-18 2012-07-26 Branum Shawn T Sulfonamides as trpm8 modulators
JP2012193176A (ja) * 2011-03-03 2012-10-11 Nippon Zoki Pharmaceut Co Ltd ミルナシプラン含有経皮吸収用医薬組成物
JP5376481B1 (ja) * 2013-03-04 2013-12-25 日本臓器製薬株式会社 経皮吸収用医薬組成物

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2029614B1 (en) * 2006-05-10 2013-01-23 Janssen Pharmaceutica, N.V. Cold menthol receptor-1 antagonists
CA3027255C (en) * 2009-07-10 2022-06-21 The General Hospital Corporation Permanently charged sodium and calcium channel blockers as anti-inflammatory agents
CN102258751A (zh) * 2011-07-21 2011-11-30 泰一和浦（北京）中医药研究院有限公司 用于治疗忧郁症、消愁解忧、善解抑郁的中药薄荷

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120190674A1 (en) * 2007-07-18 2012-07-26 Branum Shawn T Sulfonamides as trpm8 modulators
US8217060B2 (en) * 2009-05-15 2012-07-10 Janssen Pharmaceutica, Nv Benzimidazole derivatives useful as TRP M8 receptor modulators
JP2012193176A (ja) * 2011-03-03 2012-10-11 Nippon Zoki Pharmaceut Co Ltd ミルナシプラン含有経皮吸収用医薬組成物
JP5376481B1 (ja) * 2013-03-04 2013-12-25 日本臓器製薬株式会社 経皮吸収用医薬組成物

Also Published As

Publication number Publication date
JP2016524609A (ja) 2016-08-18
CN105263481A (zh) 2016-01-20
AU2014270339A1 (en) 2015-10-08
EP3003294A1 (en) 2016-04-13
CA2908378A1 (en) 2014-11-27
BR112015028884A2 (pt) 2017-07-25
US20160108005A1 (en) 2016-04-21

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